Joint dysfunctions affect a very large portion of the population. Sufficient biolubrication is a prerequisite for proper joint mobility, which is crucial for prevention and amelioration of degradative changes of the joint1.
A common joint dysfunction is osteoarthritis, with prevalence exceeding 20 million in the United States alone2. The etiology of osteoarthritis is multifactorial, including inflammatory, metabolic and mechanical causes3-5. Among the list of risk factors involved are age, gender, obesity, occupation, trauma, atheromatous vascular disease and immobilization1, 3-7, osteoarthritis may arise as a result of articular cartilage breakdown; or conversely, subchondral bone sclerosis may actually precede cartilage degeneration and loss8, 9. Once articular cartilage is injured, damage progresses10.
Current treatment focuses on reducing overloading of joints, physical therapy, and alleviation of pain and inflammation, usually by systemic or intra-articular administration of drugs11.
Articular cartilage forms a smooth, tough, elastic and flexible surface that facilitates bone movement. The synovial space is filled with the highly viscous synovial fluid (SF), containing hyaluronic acid (HA) and the glycoprotein lubricin12-14. HA is a polymer of D-glucuronic acid and D-N-acetylglucosamine, which is highly unstable and degrades under the inflammatory conditions of osteoarthritis15, 16. Lubricin is composed of ˜44% proteins, ˜45% carbohydrates and ˜11% phospholipids (PL)12-14, of which ˜41% are phosphatidylcholines (PCs), ˜27% phosphatidylethanolamines (PE) and ˜32% sphingomyelins17-19. These PL are referred to as “surface-active phospholipids” (SAPL). The PE and PC of SAPL contain two hydrocarbon chains, one of which is the monounsaturated oleic acid (18:1).
Many studies are found in the literature on the effect of SAPL on joint friction, but only a few of them deal with wear. Due to problems of acquiring suitable human specimens and the complicated nature of the experiments, most of the studies addressing this issue used animal cartilage.
Boundary lubrication, in which layers of lubricant molecules separate opposing surfaces, occurs under loading of articular joints17, 18, 20. Several different substances have been proposed as the native boundary lubricants in articular cartilage. In the past, HA was thought to be the major lubricant21, however, a recent tribiological study states that HA “by itself . . . is not responsible for the nearly frictionless boundary biolubrication found in articular cartilage”, but may contribute to load bearing and wear protection22. Many reports have shown lubricin to play the major role in the lubricating properties of synovial fluid12, 14, 19, 20, 23, 24. Pickard et al25 and Schwartz and Hills19 demonstrated that phospholipids defined as surface active phospholipids (SAPL) of lubricin facilitate joint lubrication in articular cartilage.
Special wear experiments58 were conducted on intact sheep knee joints of which some were injected with lipid solvent prior to the wear tests. The wear progression of the ‘naturally worn’ joints was compared with that of the ‘artificially worn’ dissolved lipid ones. It was found that severe depletion of the SAPL layer, which is strongly related to osteoarthritis, resulted in accelerated wear of the articular cartilage. It was concluded that the lipid layer acts as a boundary lubricant and is critically important to the proper functioning of synovial joints. In another wear test59, artificially worn lipid-depleted sheep knee joints were injected with two concentrations of the phospholipid dipalmitoyl phosphatidylcholine (DPPC) and worn further. The results indicated that a solution of DPPC may decrease cartilage wear in synovial joints.
Cartilage surfaces of human osteoarthritis hip and knee joints, which were replaced by artificial ones, showed deficiency of the outermost lubricating layer of SAPL60.
Hills et al.17 demonstrated that osteoarthritis joints have a SAPL deficiency, and that injection of the surface-active phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) into joints of osteoarthritis patients resulted in mobility improvement lasting up to 14 weeks26 without major side effects27. In another study, utilizing a unique cryogenic cartilage preservation technique, Watanabe et al. observed lipidic globular vesicles on the surface of healthy cartilage, which are assumed to play a major role in lubrication28. Kawano et al.29 and Forsey et al.30, using animal models, have shown that use of high molecular weight HA (˜2000 kDa) combined with DPPC improved lubricating ability. DPPC in the form of multilamellar vesicles (MLV) has a phase transition temperature in which solid ordered (SO) to liquid disordered (LD) phase transition occurs of 41.4° C.
U.S. Pat. No. 6,800,298 discloses dextran-based hydrogel compositions containing lipids, particularly phospholipids, for lubrication of mammalian joints.
International patent applications publications Nos. WO2003/00019063, WO2004/04779264 and WO2002/07844565 describe liposomal formulations for intraarticular delivery of active ingredients, such as steroids so as to treat an inflammatory condition.
Recently, Klein et al.31 summarized various issues of joint lubrication at the molecular level. They point to the potential role of highly-hydrated brush-like charged macromolecules at the surface of cartilage as major contributors to cartilage lubrication31-33.